Schizophrenia and brain evolution (plus bold adjectives)

When exploring the etiology of schizophrenia, a feat that has mostly eluded understanding for over 100 years, a common denominator emerges in that associated deficiencies are rooted in cognitively demanding tasks. One suggestion is that, where schizophrenic individuals are involved, disorganised thoughts, abnormal speech, auditory hallucinations and paranoid delusions are symptomatic consequences of our haphazardly evolved brains. It might not seem revelatory, nor is it a particularly new thought on the matter, yet this disorder clearly has ties with human-specific, recently evolved behaviours, such as language and social relationships. And it is here in which our problem emerges: we don’t even know how language or social relationships evolved. In fact, the evolution of the human brain is still very much an enigma, despite the whole host of literature having you believe otherwise. As Darwin put it: “Ignorance more frequently begets confidence than does knowledge[…]”.

Addressing such concerns is a relatively recent paper by Khaitovich et al (2008) in Genome Biology. Specifically, they focus on differences in gene expression and metabolite concentrations found in schizophrenia, using these to explore our brain’s approximately three-fold increase over 5-7 million years; a relatively short amount of evolutionary time, given the cognitive differences between us and chimpanzees (though encephalization is not the only indicator of increased cognitive abilities).

The team highlight 22 biological processes underlying a small portion of the mRNA expression levels in human brains. Importantly, these biological processes likely arose due to positive selection, and as such are ideal candidates in searching for any molecular differences in schizophrenic patients. To do this, the team simply (loosely applied, I admit) cross-compared these two datasets to see if there are any significant differences in the molecular profiles of schizophrenic patients. Of these biological processes, the team find six that are seemingly associated with schizophrenia (see figure 1, below). Explaining the poignancy of these findings, Khaitovich et al write:

Strikingly, all six of these biological processes are related to energy metabolism. This is highly unexpected, given that there were only 7 biological processes containing genes involved in energy metabolism among the 22 positively selected categories [my emphasis].

When bold adjectives, such as strikingly, appear in an academic paper, it is normally indicative of almost orgasmic excitement; comparable to a (non-academic) person jumping up and down after they’ve won the lottery (or this kid). Digressions aside; finding such a strong relationship is, to hijack another of the authors’ adjectives, unexpected, but not necessarily unorthodox. An increase in brain size inherently needs to be compensated by increased metabolic turnover, meaning that, at some point in our evolutionary history, genes involved in our metabolic pathways were positively selected. But still, to discover these six biological processes, — all of which relate to energy metabolism –, being differentially expressed in schizophrenic patients, is a very tempting find indeed.

Figure 1: The proportion of biological processes showing evidence of recent positive selection on the human lineage that is differentially expressed in schizophrenia. The height of the bar represents the number of GO groups showing evidence of recent positive selection on the human lineage; (a) all 22 and (b) the 7 relating to energy metabolism. The darker shade of color represents the number of GO groups differentially expressed in schizophrenia among the 22 or the 7 GO groups (Wilcoxon rank sum test, p < 0.03, FDR = 11%). Left bar, expected by chance; right bar, observed. (Khaitovich et al., 2008.)

Metabolite Concentrations

To help elucidate on these matters, the team then contrast metabolite concentrations in the pre-frontal cortex (PFC) of four groups: schizophrenic patients; healthy control subjects; chimpanzees; and, rhesus macaques. In bringing our evolutionary cousins to the party, the authors are able to show a clear divergence in metabolite concentrations on human and chimpanzee lineages (with the rhesus macaques having split from an older common ancestor, and should therefore also show a different metabolite profile). The rationale here is that primates only allocate around 13% of their total energy to the brain, compared to our mighty 20%. Additionally, the PFC itself makes an ideal location, primarily for two reasons: 1) Schizophrenic individuals normally show structural abnormalities, indicated by reduced blood flow (neural activity) in the PFC; 2) Cytoarchitectural components of the PFC are phylogenetically younger in humans, especially Broadmann area 46 (where the team collected their metabolite samples from), which almost certainly evolved after the human-Chimpanzee divergence.

As expected, metabolite concentrations show distinct biochemical profiles in all four instances (see figure 2, above), with the “altered metabolites play[ing] key roles in energy metabolism (creatine, lactate) neurotransmission (choline, glycine) and lipid/cell membrane metabolism” . These metabolites are host to a whole array of metabolically expensive brain functions; for instance, inhibiting glycine production in mice causes morph0logical changes to their PFC. These observed differences, in both gene expression and metabolite concentrations, suggests that the human brain is at “the limit of its metabolic capacities”. Therefore, impediments to these metabolic functions has severe consequences, with schizophrenia being one such instance.

I’m not too surprised by the notions put forward in this paper. A previous study found potential correlations between certain gene variations, for example DISC1, and individuals with schizophrenic symptoms. Also, given that schizophrenia persistently exists in around 1% of population, and despite affected individuals rarely reproducing, it suggests this thought disorder is inextricably linked with some important, functionally salient adaptation. For Khaitovich et al this link is brain metabolism.

We must note, however, that both schizophrenia and evolutionary studies conducted so far, including the study presented here, provide no direct link between metabolic changes, such as changes in energy metabolism, and cognitive phenotype.

So, for now at least, we can make some subtle inferences from the research presented, and remain relatively optimistic that this research route will be emulated in future studies.

N.B. I’ve just come across a related post over at The Corpus Callosum, which argues we are conflating two different types of impairments under the banner of schizophrenia. Here’s the paper the post is referring, though I haven’t yet had time to read it for myself. I’ll let you known my thoughts if I have anything to add.